This invention relates to the industrial manufacture of alkaline earth metal stearate compositions useful as industrial lubricants for uses including metal forming and tablet formulation of pharmaceutical preparations. More particularly, this invention relates to a process for preparing magnesium stearate lubricant exhibiting improved properties in lubrication and dissolution of pharmaceutical preparations in tablet form.
Numerous patents disclose the utility of stearates as lubricants or powder flow enhancers. U.S. Pat. Nos. 6,437,000, 5,032,632, 5,952,004, 5,447,729, 4,800,082, 4,777,080 and U.S. Published Application 2002/0052411 provide typical disclosures of such utility.
The use of magnesium stearate as a pharmaceutical tableting lubricant is well known in the art. According to USP/NF (2004), magnesium stearate is described as a substance containing at least 40% stearic acid, 90% as the sum of stearic acid and palmitic acid, and not more than 6.0% water. Magnesium stearate commonly used in pharmaceutical applications is a mixture of magnesium stearate and magnesium palmitate, since sources used to derive magnesium stearate include tallow, palm oil, and soybean oil, all of which are glyceryl esters of C16 and C18 fatty acids. Moreover, the state of magnesium stearate may be amorphous, or exhibit any of the following crystalline forms—anhydrous, monohydrate, dihydrate, and trihydrate. The USP/NF description of the composition and attributes of magnesium stearate does not account for functionality differences of the various crystalline forms. Further, the water content of up to 6.0% allows for products containing many possible combinations of hydrated forms to meet the requirements in the compendial monograph.
Pharmaceutical manufacturers and researchers have found that of the three polymorphic hydrates (mono-, di- and tri-), the dihydrate form is preferred as it provides superior lubricating properties. It is also known that the content of water and the resulting crystal forms contribute to functionality of magnesium stearate. Magnesium stearate compositions that contain some dihydrate are perceived to have advantages in the formulation and manufacture of solid dosage forms. It has been reported that improvements in disintegration, dissolution, crush strength and extrusion force are related specifically to the presence of dihydrate as opposed to other hydrated forms of magnesium stearate. Dihydrate has been reported to have the best anti-caking properties.
However, the prior art has failed to describe a method to manufacture the dihydrate from a mixed fatty acid composition that typifies commercial sources in terms of its stearic acid/palmitic acid content, nor a method for preparing it. There is no description in the prior art to suggest that commercial fatty acids have the correct composition to obtain pure dihydrate, or even significant amounts of dihydrate. The lack of consistency in commercial fatty acid compositions make controlling the content of dihydrate in the finished product challenging. The dihydrate is not an intermediate substance in the formation of the trihydrate from the anhydrous form when it was exposed to high humidity, and is only crystallized from solution under certain circumstances.
Further, currently available magnesium stearate compositions have the potential to adversely affect pharmacological activity by providing a water repellant barrier to dissolution of drugs, and can have a major influence on bioavailability, particularly of sustained release drugs.
In order for the pharmaceutical industry to gauge the potential benefits of the dihydrate form for the purpose of creating new formulations based on these findings, pure or at least well-defined compositions containing dihydrate material must ultimately become commercially available.
Commercially available magnesium stearate is actually a mixture of magnesium stearate and palmitate, and the hydration and degree of crystallinity vary significantly depending upon the manufacturing process, as well as from batch to batch depending on the starting materials. While high-purity forms of magnesium stearate dihydrate or magnesium palmitate dihydrate have been prepared and characterized in the laboratory, there are no commercially viable methods available for the preparation of the preferred dihydrate form.
Improvements and efficiencies in the industrial preparation of stearate salts have been the subject of considerable research. As the number and use of medications, particularly in tablet form, expands, so to does the demand for ingredients employed in pharmaceutical tablet formation as well as in industrial operations. One such industrial application is metalworking that has also increased demand for reasonable priced lubricants of the stearate class, as is found in U.S. Pat. No. 5,277,832.
Another attempt to gain efficiency and an improved product is disclosed in U.S. Pat. No. 5,175,322. This patent discloses a continuous process for manufacturing alkaline earth metal stearate soaps by the double decomposition method wherein a stream of an alkaline earth metal soap and an inorganic metal salt is dropped on a moving impeller of a mixer thereby instantaneously mixing the reactant together followed by rapid discharge from the reactor of the newly formed stearate salt. This process is purported to provide a product free of unreacted starting materials and unwanted by-products. An improved double decomposition reaction was disclosed in U.S. Pat. No. 5,434,277 wherein it is disclosed that such reactions do not provide high purity products because of the presence of unreacted starting materials present in the product. The solution to this problem according to this disclosure is to provide alternated basification-acidification of the reaction mixture. The effectiveness of the alternate treatment of the reaction mixture was shown by DSC analysis of the product indicating the disappearance of stearic acid starting material after alternative treatment. None of the prior disclosures mention the relevance of stearic acid/palmitic acid composition impacting hydration nor any means to control hydration of precipitated stearates in aqueous media.
A publication entitled “The Magnesium Stearate Problem” originally presented as a paper in 1992 and then published in Manufacturing Chemist, December 1993 discloses a study of the variations in lubricant properties of products from various industrial batches of stearate that has been observed in the industry. The observed variations were reported by K. J. Steffens and J. Koglin in an attempt to determine the unexplained cause of performance variation of industrial production batches of stearate salt that seemed identical based on the manufacturers reported attributes. Significant variations were observed among the commercial sources with respect to lubrication and tablet properties.
The writers classified commercial grades of magnesium stearate into six types distinguished by differences in their hydration and crystallinity. It was determined that crystalline magnesium stearate containing “predominately dihydrate form” was clearly superior when used as lubricant in a model formulation. Unfortunately, no method of manufacturing the pure dihydrate phase has been described in the literature, with the exception of synthesis from relatively pure stearic acid, which is cost prohibitive.
It is therefore desirable to provide an alkaline earth metal stearate composition and related method of production that result in consistent production of the dihydrate form of the alkaline earth metal stearate.